rs4149584 — TNFRSF1A R92Q

Missense variant in TNF receptor 1 that causes low-penetrance TRAPS (recurrent fever syndrome) and independently raises multiple sclerosis risk ~1.6-fold via stronger TNF binding and altered receptor trafficking

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TNFRSF1A R92Q — The TNF Receptor Variant That Bridges Periodic Fever and MS

The TNFRSF1A gene encodes TNF receptor 1 (TNFR1), the primary signaling receptor for tumor necrosis factor-alpha (TNF-α), a master inflammatory cytokine expressed on virtually every nucleated cell in the body. When TNF-α binds TNFR1, it can trigger cell death, inflammation, immune activation, or in certain tissue contexts, tissue repair — making the receptor's tight regulation essential. The R92Q variant (rs4149584) substitutes glutamine for arginine at position 92 of the mature protein, altering how the receptor binds TNF-α and how it traffics through the cell. The consequence is a SNP with two distinct clinical faces: a rare but recognized autoinflammatory disorder called TRAPS11 TRAPS
TNF Receptor-Associated Periodic Syndrome — characterized by recurrent, self-limiting episodes of fever, serositis, rash, and musculoskeletal pain lasting days to weeks at one end, and a modest but independently established risk for multiple sclerosis at the other.

The Mechanism

Arginine at position 92 sits in the cysteine-rich domain (CRD1) of TNFR1's extracellular region — not at the TNF-α binding interface directly, but within a domain important for receptor folding and trafficking. Molecular dynamics simulations22 Molecular dynamics simulations
Agulló et al. (2015) modeled the R92Q variant and found the mutation substantially reshapes the receptor-ligand interaction geometry show that the R92Q substitution expands the contact area between TNFR1 and TNF-α from 1,070 Ų to 1,388 Ų, tightening the interaction and reducing the receptor-ligand distance from 28.7 to 27.9 Å. At the same time, in cell-based transfection experiments, R92Q protein fails to reach the plasma membrane33 R92Q protein fails to reach the plasma membrane
Gomez-Pinedo et al. (2022) showed R92Q protein accumulates in the endoplasmic reticulum of oligodendroglioma cells rather than trafficking to the cell surface efficiently — it accumulates in the endoplasmic reticulum (ER) instead of being delivered to the cell surface. This ER retention has two consequences: first, it reduces cell-surface TNFR1 signaling capacity; second, it may activate the unfolded protein response, a pathway that itself drives inflammation. The net effect in carriers appears to be paradoxically elevated soluble TNF-R1 in serum — Comabella et al. found44 Comabella et al. found
Comabella et al. Neurology 2013 measured sTNF-R1 in 2,032 MS patients; R92Q carriers had significantly higher circulating sTNF-R1 (p=0.003) and elevated full-length TNFRSF1A mRNA (p=0.011) significantly higher circulating sTNF-R1 levels in R92Q carriers (p=0.003), along with upregulated TNFRSF1A mRNA. Increased caspase-3 (CASP3) mRNA expression in R92Q carriers suggests heightened apoptotic signaling downstream of the receptor.

TRAPS: Recurrent Fever From a Leaky Immune Brake

TRAPS was first described as a dominant disorder caused by rare, high-penetrance mutations in TNFRSF1A — particularly those disrupting cysteine residues in the extracellular domain, which severely misshape the receptor. R92Q sits in a distinct mechanistic category: a low-penetrance TRAPS variant55 low-penetrance TRAPS variant
ClinVar classifies R92Q as "conflicting classifications" — 9 submissions call it benign, 7 call it uncertain significance, reflecting its low penetrance and variable expressivity across families with incomplete penetrance, variable expressivity, and a much milder phenotype than classic TRAPS. When R92Q does cause autoinflammatory symptoms, carriers experience episodic fever lasting days to weeks, arthralgias, myalgias, urticarial skin rash, and severe fatigue — clinically indistinguishable from classic TRAPS but milder and typically adult-onset rather than childhood-onset. Kümpfel et al. (2008)66 Kümpfel et al. (2008)
Kümpfel et al. Neurology 2008 — 21 MS patients with R92Q, all showing TRAPS-compatible symptoms; clinical severity was milder than typical TRAPS found that among 21 MS patients carrying R92Q, all exhibited TRAPS-compatible symptoms — mainly myalgias, arthralgias, headache, severe fatigue, and skin rashes. A dose-effect study77 dose-effect study
Grandemange et al. Mol Genet Genomic Med 2017 — first documentation of R92Q homozygosity producing more severe TRAPS-like phenotype than heterozygosity found that homozygous R92Q individuals show more severe autoinflammatory presentations than heterozygotes, suggesting the variant's autoinflammatory effects are dosage-sensitive.

The Evidence for MS Risk

R92Q emerged from multiple genome-wide and candidate-gene association studies as an independent MS susceptibility variant. A GWAS meta-analysis88 GWAS meta-analysis
Caminero et al. Clin Exp Immunol 2011 — aggregated GWAS data identifying R92Q as MS risk factor with OR=1.6 assigned an odds ratio of 1.6 for MS. A Belgian replication study — 967 MS patients versus 1,022 controls99 967 MS patients versus 1,022 controls
Goris et al. J Neuroimmunol 2011 (p=5×10⁻⁴), finding R92Q in 3% of MS patients vs 1% of controls — found the variant in 3% of MS cases versus 1% of controls, yielding OR=2.26 (95% CI 1.41–3.61), and confirmed this association was independent of the common splice-region variant rs1800693 in the same gene. The two variants are not in strong linkage disequilibrium (r²≈0.041 in Europeans) and represent mechanistically distinct signals. Comabella et al.1010 Comabella et al.
Comabella et al. Neurology 2013 — 2,032 MS patients, showing R92Q carriers had younger disease onset and slower progression found R92Q carriers had younger age at MS onset and, notably, slower disease progression compared to non-carriers — suggesting the variant may influence disease trajectory as well as susceptibility. The pediatric MS literature adds further weight: Blaschek et al. (2018)1111 Blaschek et al. (2018)
Blaschek et al. Eur J Paediatr Neurol 2018 — 29 pediatric MS patients, R92Q detected in 6/11 mutation-positive cases; SMR 4.6–13.6 depending on reference population found R92Q in 6 of 29 childhood-onset MS patients with a standardized morbidity ratio of 4.6–13.6 relative to expected population frequency.

Practical Actions

For most carriers, the MS risk contribution from a single T allele is modest (OR~1.6–2.3) and does not require clinical intervention beyond awareness. However, carriers who also develop unexplained episodic fever, joint pain, or rash should raise the possibility of low-penetrance TRAPS with their physician — the diagnosis changes management meaningfully. Colchicine is often effective for TRAPS symptom control in mild cases, while anti-IL-1 biologics (anakinra, canakinumab) are used for refractory cases. Critically, standard anti-TNF biologics used in rheumatology (infliximab, adalimumab, etanercept) are generally contraindicated in TRAPS — they can paradoxically worsen autoinflammatory flares, and in any TNFRSF1A variant carrier, they carry elevated neurological risk. Homozygous TT carriers (extremely rare, ~0.01% of the population) have a meaningfully elevated risk of both autoinflammatory disease and MS and warrant referral to an autoinflammatory specialist regardless of current symptoms.

Interactions

R92Q (rs4149584) and the splice-region variant rs1800693 in the same gene are mechanistically independent signals. rs1800693 generates a soluble Δ6-TNFR1 decoy isoform that sequesters TNF-α; R92Q generates a full-length receptor with tighter TNF-α binding but impaired cell-surface trafficking. The two mechanisms could theoretically combine: one reducing membrane receptor density (R92Q via ER retention), the other generating a competing soluble decoy (rs1800693 Δ6 isoform). Compound carriers of both risk alleles have not been formally studied for MS risk but are expected to carry additive susceptibility from independent mechanisms. Clinicians should consider both variants when evaluating TNFRSF1A-related disease risk.

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard TNFR1 Function Normal

No R92Q variant — standard TNF receptor 1 structure and function

You carry two copies of the common C allele (arginine at position 92), meaning your TNFR1 receptor has the standard structure at this position. You do not carry the R92Q variant associated with TRAPS or the modest additional MS susceptibility this variant confers. This is the common genotype — approximately 97–98% of people of European ancestry share it. Your TNFRSF1A risk profile from this locus is neutral.

CT R92Q Carrier Intermediate

One copy of R92Q — low-penetrance autoinflammatory risk and modest MS susceptibility

The R92Q variant sits in the cysteine-rich domain of TNFR1's extracellular region. Molecular dynamics studies show it expands the TNF-α contact area by ~30% (1,070→1,388 Ų) and reduces receptor-ligand distance, tightening TNF binding. Simultaneously, cell-based experiments show the mutant protein accumulates in the endoplasmic reticulum rather than reaching the plasma membrane, reducing functional cell-surface TNFR1 density. Carriers show elevated circulating soluble TNF-R1 (p=0.003) and upregulated TNFRSF1A mRNA.

For MS, Goris et al. (2011) found R92Q in 3% of 967 MS patients versus 1% of 1,022 controls, yielding OR=2.26. Comabella et al. (2013) observed R92Q carriers had younger MS onset but slower progression. These associations are independent of the splice-region variant rs1800693 in the same gene.

For TRAPS: heterozygous R92Q carriers who develop autoinflammatory features typically present in adulthood with episodic fever (lasting days to weeks), myalgias, arthralgias, urticarial rash, and fatigue. Symptoms are milder than classic TRAPS caused by high-penetrance cysteine mutations. Penetrance is incomplete — many carriers are entirely asymptomatic.

TT Homozygous R92Q High Risk

Two copies of R92Q — substantially elevated autoinflammatory risk and higher MS susceptibility

Grandemange et al. (2017) documented the first R92Q dose effect: a proband homozygous for R92Q showed more severe TRAPS-like presentation than heterozygous family members in one family, while heterozygous parents in a second family were asymptomatic — illustrating the variable expressivity but real dosage sensitivity of this variant. Gomez-Pinedo et al. (2022) showed that R92Q protein accumulates in the endoplasmic reticulum rather than the cell surface; in homozygotes, no wild-type TNFR1 is available to compensate for this trafficking defect.

The MS risk from two copies of R92Q has not been quantified independently, but the additive model from heterozygote data (OR~2.26 per allele) suggests substantially elevated risk for this rare genotype. In a study of 138 individuals from families with multiple MS-affected members, two homozygous R92Q patients came from the same family — consistent with familial aggregation of this rare genotype.

Clinical management should involve both a rheumatologist or autoinflammatory specialist (for TRAPS monitoring) and a neurologist (for MS surveillance). Standard anti-TNF biologics are strongly contraindicated.